The present invention is based upon the discovery that benzofuran-7-carboxamides, and related compounds, and, more particularly, pyrrolidinyl and quinuclidinyl derivatives thereof exhibit strong anxiolytic activity.
Commonly assigned U.S. Pat. No. 4,888,353 to Lednicer discloses a novel group of compounds including benzofurancarboxamides and dihydrobenzofurancarboxamides and their quinuclidinyl derivatives which are useful as antiemetic and antipsychotic agents.
It has previously been disclosed in U.S. Pat. No. 4,857,517 to Youssefyeh that certain quinuclidinyl benzoxepins such as 6-amino-7-chloro-9-N-(1-azabicyclo[2.2.2]octan -3-yl)carboxamido-2,3,4,5-tetrahydro-1-benzoxepin are 5HT.sub.3 antagonists and are considered to be useful in the treatment of schizophrenia, anxiety and migraine. European Application 0 307 172 discloses that certain benzofurancarboxamides such as endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo [3.2.1] oct-3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate and 2,3-dihydro-5-chloro-2,2-dimethyl-N-(1-azabicyclo[2.2.2] oct -3-yl-7-benzofuran carboxamide (Z)-2-butenedioate are 5HT.sub.3 antagonists.
According to Gardner, "Potential use of Drugs Modulating 5HT Activity in the Treatment Anxiety," Gen Pharmacol, 1988 19(3) p 347-56, while it has been suggested that 5HT mediated systems may be involved in modulating anxiety, the premise has been questioned and the mechanism remains unknown. 5-Hydroxytryptophan (5HT), also known as Serotonin, is found throughout the body and is involved in a large number of physiological processes related to a variety of different receptors found on the surface membranes of cells in different body tissues There appear to be a large number of 5HT receptor types, some experts estimating there may be in excess of 20, and some drugs are believed to have different effects on different receptors all of which contribute to the overall effect of the drug. Consequently, the physiological activity of 5HT antagonists remains highly unpredictable.
Accordingly, while it has been claimed that certain carboxamides are 5HT.sub.3 antagonists and possess anxiolytic activity, this does not indicate that there is even a strong likelihood that other 5HT.sub.3 antagonists will relieve anxiety. For example, File and Johnston, Psychopharmacology, (1989) 99: 248-251 report that three 5HT.sub.3 antagonists including A. H. Robin's Zacopride had no significant effect on social interaction in the elevated plug-maze test in the rat.